Skip to main content
Top
Published in: Virchows Archiv 3/2005

01-09-2005 | Original Article

Tracing origin of serrated adenomas with BRAF and KRAS mutations

Authors: Eui Jin Lee, Chan Choi, Cheol Keun Park, Leeso Maeng, Jehoon Lee, Anhi Lee, Kyoung-Mee Kim

Published in: Virchows Archiv | Issue 3/2005

Login to get access

Abstract

Serrated neoplasm of the colorectum raised many as-yet unanswered issues. To characterize serrated neoplasia pathway, we investigated BRAF and KRAS mutations in 35 traditional serrated adenomas. BRAF exons 11 and 15, and KRAS exon 2 were amplified by polymerase chain reaction and directly sequenced. BRAF V599E mutation was found in 27 serrated adenomas (77.1%), and KRAS mutations were found in 3 (8.6%) of 35 traditional serrated adenomas. In 13 cases, mixed polyps composed of traditional serrated adenomas and hyperplastic (serrated) polyps were observed, and seven of them showed the same BRAF mutations in both components. Somatic mutations of BRAF and KRAS genes were mutually exclusive. These findings suggest that BRAF mutations are early and a critical event in the serrated adenomas, and most serrated adenomas in both sides of colon may progress from microvesicular hyperplastic polyps via BRAF mutations, and some left-sided serrated adenomas develop via KRAS mutations.
Literature
1.
go back to reference Ajioka Y, Watanabe H, Jass JR, Yokota Y, Kobayashi M, Nishikura K (1998) Infrequent K-ras codon 12 mutation in serrated adenomas of human colorectum. Gut 42:680–684PubMed Ajioka Y, Watanabe H, Jass JR, Yokota Y, Kobayashi M, Nishikura K (1998) Infrequent K-ras codon 12 mutation in serrated adenomas of human colorectum. Gut 42:680–684PubMed
2.
go back to reference Bariol C, Hawkins NJ, Turner JJ, Meagher AP, Williams DB, Ward RL (2004) Histopathological and clinical evaluation of serrated adenomas of the colon and rectum. Mod Pathol 16:417–423CrossRef Bariol C, Hawkins NJ, Turner JJ, Meagher AP, Williams DB, Ward RL (2004) Histopathological and clinical evaluation of serrated adenomas of the colon and rectum. Mod Pathol 16:417–423CrossRef
3.
go back to reference Chan TL, Zhao W, Leung SY, Yuen ST (2003) BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 63:4878–4881PubMed Chan TL, Zhao W, Leung SY, Yuen ST (2003) BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 63:4878–4881PubMed
4.
go back to reference Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954CrossRefPubMed Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954CrossRefPubMed
5.
go back to reference Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM (2004) Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol [Epub ahead of print] Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM (2004) Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol [Epub ahead of print]
6.
go back to reference Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, Sekikawa K, Hagiwara K, Takenoshita S (2003) BRAF mutations in papillary carcinomas of the thyroid. Oncogene 322:6455–6457CrossRef Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, Sekikawa K, Hagiwara K, Takenoshita S (2003) BRAF mutations in papillary carcinomas of the thyroid. Oncogene 322:6455–6457CrossRef
7.
go back to reference Hawkins NJ, Bariol C, Ward RL (2002) The serrated neoplasia pathway. Pathology 34:548–555PubMed Hawkins NJ, Bariol C, Ward RL (2002) The serrated neoplasia pathway. Pathology 34:548–555PubMed
8.
go back to reference Higashidani Y, Tamura S, Morita T, Tadokoro T, Yokoyama Y, Miyazaki J, Yang Y, Takeuchi S, Taguchi H, Onishi S (2003) Analysis of K-ras codon 12 mutation in flat and nodular variants of serrated adenoma in the colon. Dis Colon Rectum 46:327–332CrossRefPubMed Higashidani Y, Tamura S, Morita T, Tadokoro T, Yokoyama Y, Miyazaki J, Yang Y, Takeuchi S, Taguchi H, Onishi S (2003) Analysis of K-ras codon 12 mutation in flat and nodular variants of serrated adenoma in the colon. Dis Colon Rectum 46:327–332CrossRefPubMed
9.
go back to reference Iino H, Jass JR, Simms LA, Young J, Leggett B, Ajioka Y, Watanabe H (1999) DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and mixed polyps: a mild mutator pathway for colorectal cancer? J Clin Pathol 52:5–9PubMed Iino H, Jass JR, Simms LA, Young J, Leggett B, Ajioka Y, Watanabe H (1999) DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and mixed polyps: a mild mutator pathway for colorectal cancer? J Clin Pathol 52:5–9PubMed
11.
go back to reference Jass JR, Young J, Leggett BA (2000) Hyperplastic polyps and DNA microsatellite unstable cancers of the colorectum. Histopathology 37:295–301CrossRefPubMed Jass JR, Young J, Leggett BA (2000) Hyperplastic polyps and DNA microsatellite unstable cancers of the colorectum. Histopathology 37:295–301CrossRefPubMed
12.
go back to reference Jass JR (2001) Serrated route to colorectal cancer: back street or super highway? J Pathol 193:283–285CrossRefPubMed Jass JR (2001) Serrated route to colorectal cancer: back street or super highway? J Pathol 193:283–285CrossRefPubMed
13.
14.
go back to reference Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, Barker MA, Arnold S, McGivern A, Matsubara N, Tanaka N, Higuchi T, Young J, Jass JR, Leggett BA (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53(8):1137–1144CrossRefPubMed Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, Barker MA, Arnold S, McGivern A, Matsubara N, Tanaka N, Higuchi T, Young J, Jass JR, Leggett BA (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53(8):1137–1144CrossRefPubMed
15.
go back to reference Koinuma K, Shitoh K, Miyakura Y, Furukawa T, Yamashita Y, Ota J, Ohki R, Choi YL, Wada T, Konishi F, Nagai H, Mano H (2004) Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer 108:237–242CrossRefPubMed Koinuma K, Shitoh K, Miyakura Y, Furukawa T, Yamashita Y, Ota J, Ohki R, Choi YL, Wada T, Konishi F, Nagai H, Mano H (2004) Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer 108:237–242CrossRefPubMed
16.
go back to reference O’Brien MJ, Yang S, Clebanoff JL, Mulcahy E, Farraye FA, Amorosino M, Swan N (2004) Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. Am J Surg Pathol 28:423–434 O’Brien MJ, Yang S, Clebanoff JL, Mulcahy E, Farraye FA, Amorosino M, Swan N (2004) Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. Am J Surg Pathol 28:423–434
17.
go back to reference Oliveira C, Pinto M, Duval A, Brennetot C, Domingo E, Espin E, Armengol M, Yamamoto H, Hamelin R, Seruca R, Schwartz S Jr (2003) BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene 22:9192–9196CrossRefPubMed Oliveira C, Pinto M, Duval A, Brennetot C, Domingo E, Espin E, Armengol M, Yamamoto H, Hamelin R, Seruca R, Schwartz S Jr (2003) BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene 22:9192–9196CrossRefPubMed
18.
go back to reference Otori K, Oda Y, Sugiyama K, Hasebe T, Mukai K, Fujii T, Tajiri H, Yoshida S, Fukushima S, Esumi H (1997) High frequency of K-ras mutations in human colorectal hyperplastic polyps. Gut 40:660–663 Otori K, Oda Y, Sugiyama K, Hasebe T, Mukai K, Fujii T, Tajiri H, Yoshida S, Fukushima S, Esumi H (1997) High frequency of K-ras mutations in human colorectal hyperplastic polyps. Gut 40:660–663
19.
go back to reference Rashid A, Houlihan PS, Booker S, Petersen GM, Giardiello FM, Hamilton SR (2000) Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 119:323–332PubMed Rashid A, Houlihan PS, Booker S, Petersen GM, Giardiello FM, Hamilton SR (2000) Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 119:323–332PubMed
20.
go back to reference Russell SE, McCluggage WG (2004) A multistep model for ovarian tumorigenesis: the value of mutation analysis in the KRAS and BRAF genes. J Pathol 203:617–619CrossRefPubMed Russell SE, McCluggage WG (2004) A multistep model for ovarian tumorigenesis: the value of mutation analysis in the KRAS and BRAF genes. J Pathol 203:617–619CrossRefPubMed
21.
go back to reference Sieben NL, Macropoulos P, Roemen GM, Kolkman-Uljee SM, Jan Fleuren G, Houmadi R, Diss T, Warren B, Al Adnani M, De Goeij AP, Krausz T, Flanagan AM (2004) In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol 202:336–340CrossRefPubMed Sieben NL, Macropoulos P, Roemen GM, Kolkman-Uljee SM, Jan Fleuren G, Houmadi R, Diss T, Warren B, Al Adnani M, De Goeij AP, Krausz T, Flanagan AM (2004) In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol 202:336–340CrossRefPubMed
22.
go back to reference Singer G, Oldt R III, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih I-M (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 395:484–486 Singer G, Oldt R III, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih I-M (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 395:484–486
23.
go back to reference Sommerer F, Vieth M, Markwarth A, Rohrich K, Vomschloss S, May A, Ell C, Stolte M, Hengge UR, Wittekind C, Tannapfel A (2004) Mutations of BRAF and KRAS2 in the development of Barrett’s adenocarcinoma. Oncogene 23:554–558CrossRefPubMed Sommerer F, Vieth M, Markwarth A, Rohrich K, Vomschloss S, May A, Ell C, Stolte M, Hengge UR, Wittekind C, Tannapfel A (2004) Mutations of BRAF and KRAS2 in the development of Barrett’s adenocarcinoma. Oncogene 23:554–558CrossRefPubMed
24.
go back to reference Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM (2003) Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 27:65–81 Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM (2003) Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 27:65–81
25.
go back to reference Wang L, Cunningham JM, Winters JL, Guenther JC, French AJ, Boardman LA, Burgart LJ, McDonnell SK, Schaid DJ, Thibodeau SN (2003) BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res 63:5209–5212PubMed Wang L, Cunningham JM, Winters JL, Guenther JC, French AJ, Boardman LA, Burgart LJ, McDonnell SK, Schaid DJ, Thibodeau SN (2003) BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res 63:5209–5212PubMed
26.
go back to reference Yang S, Farraye FA, Mack C, Posnik O, O’Brien MJ (2004) BRAF and KRAS mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol 28(11):1452–1459 Yang S, Farraye FA, Mack C, Posnik O, O’Brien MJ (2004) BRAF and KRAS mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol 28(11):1452–1459
27.
go back to reference Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS, Futreal PA, Stratton MR, Wooster R, Leung SY (2002) Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62:6451–6455PubMed Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS, Futreal PA, Stratton MR, Wooster R, Leung SY (2002) Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62:6451–6455PubMed
Metadata
Title
Tracing origin of serrated adenomas with BRAF and KRAS mutations
Authors
Eui Jin Lee
Chan Choi
Cheol Keun Park
Leeso Maeng
Jehoon Lee
Anhi Lee
Kyoung-Mee Kim
Publication date
01-09-2005
Publisher
Springer-Verlag
Published in
Virchows Archiv / Issue 3/2005
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-005-1226-2

Other articles of this Issue 3/2005

Virchows Archiv 3/2005 Go to the issue

Announcements

September 2005